The studies outlined in this proposal involve both clinical and laboratory investigations. We plan to explore the mechanisms responsible for hypobetalipoproteinemia in patients obligate for heterozygous hypobetalipoproteinemia and to compare these results with those in patients with familial hypobetalipoproteinemia (who are not obligate heterozygotes). These will involve in vivo studies of 125I-LDL turnover, sterol balance and cholesterol absorption as well as in vitro studies of apoprotein patterns (CIII-1 and CIII-2 ratios, apo E isoproteins and apoprotein B heterogeneity). We will also examine whether or not dietary cholesterol will influence the concentrations of plasma lipids and lipoproteins of these patients and its effect on LDL metabolism. Considerable insight into the role of LDL in cellular metabolism can be gained from studies in patients who lack this lipoprotein (abetalipoproteinemia). Recent studies by the PI have documented increased total body synthesis of cholesterol in three patients with this disorder but the mechanisms by which these patients regulate cholesterol metabolism are not known. Further studies in these three patients with phenotypic abetalipoproteinemia aim to examine how a complete deficiency of all apoprotein B-containing lipoproteins influences steroid hormone production (under both basal and stimulated conditions), bile composition and the activity of lipoprotein and hepatic lipase. Corollary studies in vitro will examine whether lipoproteins present in the plasma of patients with abetalipoproteinemia (which contain apo E) can bind to the LDL receptor and thereby supply cholesterol to cells in tissue culture. Overall, these studies should add to our knowledge of the role of LDL in cellular metabolism as well as further delineate the pathophysiology of abetalipoproteinemia and hypobetalipoproteinemia.